Gut Microbiome in Serious Mental Illnesses: a Systematic Review and Critical Evaluation
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UC San Diego UC San Diego Previously Published Works Title Gut microbiome in serious mental illnesses: A systematic review and critical evaluation. Permalink https://escholarship.org/uc/item/2nx0z5sd Authors Nguyen, Tanya T Hathaway, Hugh Kosciolek, Tomasz et al. Publication Date 2021-08-01 DOI 10.1016/j.schres.2019.08.026 Peer reviewed eScholarship.org Powered by the California Digital Library University of California SCHRES-08457; No of Pages 17 Schizophrenia Research xxx (xxxx) xxx Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres Gut microbiome in serious mental illnesses: A systematic review and critical evaluation Tanya T. Nguyen a,i,⁎, Hugh Hathaway b,c, Tomasz Kosciolek c,d, Rob Knight c,e,f,g, Dilip V. Jeste a,g,h,i a Department of Psychiatry, University of California San Diego, CA, United States of America b Medical Sciences Division, University of Oxford, Oxford, United Kingdom c Department of Pediatrics, University of California San Diego, CA, United States of America d Małopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland e Department of Computer Science and Engineering, University of California San Diego, CA, United States of America f Department of Bioengineering, University of California San Diego, CA, United States of America g Center for Microbiome Innovation, University of California San Diego, CA, United States of America h Department of Neurosciences, University of California San Diego, CA, United States of America i Sam and Rose Stein Institute for Research on Aging, University of California San Diego, CA, United States of America article info abstract Article history: Schizophrenia and bipolar disorder (BD) are associated with debilitating psychiatric and cognitive dysfunction, Received 20 June 2019 worse health outcomes, and shorter life expectancies. The pathophysiological understanding of and therapeutic Received in revised form 19 August 2019 resources for these neuropsychiatric disorders are still limited. Humans harbor over 1000 unique bacterial spe- Accepted 22 August 2019 cies in our gut, which have been linked to both physical and mental/cognitive health. The gut microbiome is a Available online xxxx novel and promising avenue to understand the attributes of psychiatric diseases and, potentially, to modify Keywords: them. Building upon our previous work, this systematic review evaluates the most recent evidence of the gut Schizophrenia microbiome in clinical populations with serious mental illness (SMI). Sixteen articles that met our selection Bipolar disorder criteria were reviewed, including cross-sectional cohort studies and longitudinal treatment trials. All studies re- First episode psychosis ported alterations in the gut microbiome of patients with SMI compared to non-psychiatric comparison subjects Bacteria (NCs), and beta-diversity was consistently reported to be different between schizophrenia and NCs. Microbes Ruminococcaceae and Faecalibacterium were relatively decreased in BD, and abundance of Ruminococcaceae Probiotics was reported across several investigations of SMI to be associated with better clinical characteristics. Lactic acid bacteria were relatively more abundant in SMI and associated with worse clinical outcomes. There was very limited evidence for the efficacy of probiotic or prebiotic interventions in SMI. As microbiome research in psychiatry is still nascent, the extant literature has several limitations. We critically evaluate the current data, in- cluding experimental approaches. There is a need for more unified methodological standards in order to arrive at robust biological understanding of microbial contributions to SMI. © 2019 Elsevier B.V. All rights reserved. 1. Introduction with SMI are prone to diseases associated with aging (Czepielewski et al., 2013; Hennekens et al., 2005; Soreca et al., 2008) and have Schizophrenia and bipolar disorder (BD) are severe neuropsychiatric twice the risk of dying from cardiovascular and gastrointestinal diseases disorders, which combined have a lifetime prevalence of 3.5% (Perälä compared to the general population (Saha et al., 2007). Physiological et al., 2007). Patients with these serious mental illnesses (SMI) face changes seen throughout the body with normal aging occur at earlier not only debilitating psychiatric and cognitive impairment but also ages, including chronic inflammation and oxidative stress, which has worse physical health outcomes and considerably shorter life expectan- led to the theoretical framework of SMI as disorders of accelerated bio- cies (Brown, 1997; Casey et al., 2009; Viron and Stern, 2010). SMI con- logical aging (Jeste et al., 2011; Kirkpatrick et al., 2008; Nguyen et al., tribute substantially to the global burden of disease (Whiteford et al., 2018a; Palmer et al., 2018; Rizzo et al., 2014). Given that lifespans are 2013) and rank among the leading causes of disability (Chong et al., generally increasing for the general population (Christensen et al., 2016) and mortality worldwide (Walker et al., 2015). Younger adults 2009), while the mortality gap for schizophrenia is growing (Lee et al., 2018), understanding the mechanisms of potential accelerated aging in SMI is imperative. ⁎ Corresponding author at: University of California San Diego, 9500 Gilman Drive #0664, La Jolla, CA 92093, United States of America. Despite decades of research, our understanding of the pathophysiol- E-mail address: [email protected] (T.T. Nguyen). ogy of these disorders is still limited. Genomic research has identified https://doi.org/10.1016/j.schres.2019.08.026 0920-9964/© 2019 Elsevier B.V. All rights reserved. Please cite this article as: T.T. Nguyen, H. Hathaway, T. Kosciolek, et al., Gut microbiome in serious mental illnesses: A systematic review and critical evaluation, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.08.026 2 T.T. Nguyen et al. / Schizophrenia Research xxx (xxxx) xxx susceptibility genes, but the results have not yet led to new therapies. seemingly discrepant findings across investigations. Although more The human gut microbiome is a dynamic population of microbes in useful insights may have been drawn from a meta-analysis of data our large intestine that form a symbiotic superorganism, with which across studies, considerable heterogeneity in study designs and meth- we have co-evolved (Dinan et al., 2014). Containing 1013 microorgan- odologies to quantify and analyze the gut microbiome and few publicly isms with over 1000 unique bacterial species containing 2 to 20 million available data from individual reports made this endeavor impractical. unique genes, the gut microbiome is a complex genomic structure with Instead, we highlighted commonalities and differences among these 100 times more genes than the human genome (Gill et al., 2006; Human investigations. Microbiome Project Consortium, 2012; Qin et al., 2010; Turnbaugh et al., 2007). Unlike the human genome, which is fixed and unchangeable, the 2. Methods gut microbiome is highly dynamic and malleable. It can be shaped by various developmental and environmental influences, such as age, ge- 2.1. Search strategy ography, cultural traditions and lifestyles (e.g., diet, cohabitation, travel), and medications (Caporaso et al., 2011; Koenig et al., 2011; We searched PubMed, PsycINFO, and Embase for articles pub- Yatsunenko et al., 2012). In fact, the overall heritability of the lished before March 7, 2019 using the following search string: microbiome is low, and the microbiomes of genetically unrelated, co- microbiome AND (schizophrenia OR psychosis OR bipolar OR serious habiting individuals is more similar than of those who are members of mental illness). Reference lists of the retrieved articles and relevant the same family but living apart (Caussy et al., 2019; Cekanaviciute review articles were cross-referenced. We examined the titles and et al., 2017; Yatsunenko et al., 2012). Furthermore, the gut metagenome abstracts of all citations and selected empirical reports based on is a better predictor of many human physical phenotypes (e.g., body our inclusion/exclusion criteria. mass index [BMI], waist circumference, glucose and high-density lipo- protein [HDL] levels, lactose consumption) than the human genome 2.2. Inclusion/exclusion criteria (Rothschild et al., 2018). Both of these characteristics of the microbiome have important implications for the development of new therapeutic Studies were selected if they met the following criteria: 1) were em- approaches. pirical studies of individuals clinically diagnosed with schizophrenia, The gut microbiome is critical in maintaining human physiology. It schizoaffective disorder, BD, or related psychotic disorders, 2) utilized regulates many metabolic processes essential for optimal health that high-throughput sequencing methods to characterize microorganisms cannot be maintained by human cells, stimulates normal immune mat- in the gut or distal large intestine, and 3) were published in English. uration, defends against pathogens, and stabilizes the gut barrier Both cross-sectional and longitudinal studies were included. We ex- (Carroll et al., 2009). SMI are characterized by increased gut permeabil- cluded review papers, meta-analyses, abstracts, case reports, and stud- ity (Severance et al., 2014, 2013, 2012). With a compromised intestinal ies exclusively using animal models. lumen, enteric microbes are exposed to systemic circulation. Gut dysbiosis may underlie the pro-inflammatory milieu and other physio-